Netrin

Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides". Netrins are genetically conserved across nematode worms, fruit flies, frogs, mice, and humans. Structurally, netrin resembles the extracellular matrix protein laminin. Netrins are chemotropic; a growing axon will either move towards or away from a higher concentration of netrin. Though the detailed mechanism of axon guidance is not fully understood, it is known that netrin attraction is mediated through UNC-40/DCC cell surface receptors and repulsion is mediated through UNC-5 receptors. Netrins also act as growth factors, encouraging cell growth activities in target cells. Mice deficient in netrin fail to form the hippocampal comissure or the corpus callosum. A proposed model for netrin activity in the spinal column of developing human embryos is that netrins are released by the floor plate and then are picked up by receptor proteins embedded in the growth cones of axons belonging to neurons in the developing spinal column. The bodies of these neurons remain stationary while the axons follow a path defined by netrins, eventually connecting to neurons inside the embryonic brain by developing synapses. Research supports that new axons tend to follow previously traced pathways rather than being guided by netrins or related chemotropic factors.

Discovery Netrin was first described in the nematode Caenorhabditis elegans in 1990, and named UNC-6, according to standard C. elegans naming protocol. The first mammalian homologue of UNC-6 was discovered in 1994, where it was discovered to be a vital guidance cue for rodent commissural axons in the spinal cord. As of 2009, five mammalian Netrins have been identified. Netrins 1, 3, and 4 are secreted proteins, whereas G1 and G2 are membrane bound proteins tethered by Glycophosphatidylinositol tails. All netrins discovered in invertebrates thus far are secreted.

Overview of netrins The netrin family is composed mostly of secreted proteins which serve as bifunctional signals: attracting some neurons while repelling others during the development of the brain. Expressed in the midline of all animals possessing bilateral symmetry, they can act as long or short range signals during neurogenesis. In order to carry out their functions, netrins interact with specific receptors: DCC or UNC-5, depending on whether they are trying to attract or repel neurons, respectively. There is a high degree of conservation in the secondary structure of netrins, which has several domains which are homologous with laminin at the amino terminal end. The C-terminal domain is where most of the variation is found between species and contains different amino acids which allow interaction with specific proteins in extracellular matrix or on the cell surface. The differences in terms of structure and function have led to the identifications of several different types of netrins including netrin-1, netrin-3, and netrins-G.

Key netrins Netrin-1 is found in the floor plate and neuroepithelial cells of the ventral region of the spinal cord, as well as other locations in the nervous system including the somatic mesoderm, pancreas and cardiac muscle. Its main role is in axonal guidance, neuronal migration and morphogenesis of different branching structures. Mice with mutations in the netrin-1 gene were observed to be lacking in forebrain and spinal cord commissural axons. Netrin-1 and -3 has been described to have an exclusive expression in cancer cells. Netrin-3 is different from other netrins. While expressed during development of the peripheral nervous system in the motor, sensory and sympathetic neurons, it is very limited in the central nervous system. Studies with netrin-3 have noticed a reduced ability to bind with DCC when compared with netrin-1. This suggests that it mainly operates through other receptors. Netrins-G are secreted but remain bound to the extracellular surface of the cell membrane through Glycophosphatidylinositol (GPI). They are expressed predominantly in the central nervous system in places such as the thalamus and mitral cells of the olfactory bulb. They do not bind to DCC or UNC-5 and instead bind to ligand NGL-1, which results in an intracellular transduction cascade. The two versions, netrin-G1 and netrin-G2, are found only in vertebrates. It is believed that they evolved independently of other netrins in order to facilitate the construction of the brain.

Netrin receptors DCC and UNC-5 proteins mediate netrin-1 responses. The UNC-5 protein is mainly involved in signaling repulsion. DCC, which is implicated in attraction, can also serve as a co-factor in repulsion signaling when far away from the source of netrin-1. DCC is highly expressed in the central nervous system and associated with the basal lamina of epithelial cells. In the absence of netrin-1, these receptors are known to induce apoptosis.

Axonal guidance Growth cones that are located at the end of developing axons during embryogenesis are responsible for the elongation of the axon during migration. Elongation occurs in response to both tropic and atropic factors present in the surrounding environment. Netrins are one such tropic factor secreted by axonal target cells that function as a crucial axonal guidance protein in both vertebrate and invertebrate organisms. Studies in multiple organisms including, mice, rats, chicks, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the zebrafish Danio rerio have indicated that secreted netrins are bifunctional, meaning that they can act as either attractants or repellants in directing axonal extension. In addition, many studies have characterized netrins as both short and long range cues, acting in the immediate or distant vicinity of their source cell (the axonal target cell).

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